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Post Traumatic Stress Disorder (PTSD) – A Primer on Neuropsychiatry and Treatment

Authors: Dr. Sanil Rege MBBS, MRCPsych, FRANZCP, Dr. James Graham PhD

November 29, 2017

Psychological trauma involves the witnessing of a traumatic or life-threatening event directly to your self or to others. The individual is likely to experience intense fear, horror and helplessness, which can result in a permanent or transient psychological wound characterized by physical, cognitive, emotional and behavioural changes.

For most, the trauma is acute and transient and results in minimal functional impairment. The psychological trauma can be classified into three clusters of symptoms. These include:

Re-experience – Flashbacks, nightmares, and intrusive thoughts Hyper-arousal – Insomnia, agitation, irritability, impulsivity, and anger Avoidance – Numbing, withdrawal, confusion, dissociation, and depression

For some, however, the syndrome persists and this is termed post-traumatic stress disorder (PTSD). A PTSD diagnosis was originally considered a normal response to an extreme situation however the presence of symptoms for an extended period of time beyond one month is indicative of an abnormal adaptation in the brain.

The prevalence of PTSD varies across countries. It occurs in 5-10% of the population and has a 2:1 female to male ratio. The gender bias may be a result of a combination of a greater propensity to lifetime violence exposure and genetic vulnerability (variation in the ADCYAP1R1 (pituitary receptor) gene). [1]

In military populations the risk is more significant. For example, 10 years after the Vietnam war, the rates of current PTSD went up to 28% in those who had experienced combat exposure. Recent analysis showed that 40 years after the end of the war, 11% of Vietnam veterans are experiencing PTSD symptoms. [1]

In civilian population samples, the rates vary from 0.2%-3.8%. A number of factors such as social supports, trauma type, and severity affect prevalence.


DIAGNOSTIC CRITERIA

The Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) recognises several criteria for a PTSD diagnosis. (see: Post Traumatic Stress Disorder – Diagnostic Interview)The PTSD criteria are as follows:

1. Exposure to stressor – The individual was either directly or indirectly (witnessing, learning, or exposure to aversive details) exposed to trauma.

2. Intrusion symptoms (one required) – The trauma is persistently re-experienced via recurrent memories, nightmares, flashbacks, psychological distress, or physiological reactivity to traumatic reminders.

3. Persistent avoidance (one required) – Avoidance of trauma-related stressors: recurrent trauma-related thoughts or environmental reminders such as people, activities, and places that act as visual reminders.

4. Negative alterations in cognition and mood (two required) – Inability to recall key features, persistent (and often distorted) negative beliefs and expectations about oneself or the world, persistent distorted blame of self or others, persistent negative trauma-related emotions, markedly diminished interest in pre-traumatic activities, feeling alienated from others and constricted affect (persistent inability to experience positive emotions).

5. Alterations in arousal and reactivity – Disturbances to arousal and reactivity that began, or worsened, after the trauma are characterised by aggression, self-destructive or reckless behaviour, hyper-vigilance, exaggerated startle response, and difficulty concentrating or sleeping.

6. Duration – Criteria B-D must be present for at least one month. 7. Functional significance – Trauma-related symptoms must cause

psychological, social, or functional impairment.

Exclusion – Trauma-related symptoms cannot be attributed to anything else such as medications or substance abuse.

However, trauma outcomes vary across individuals, and this appears to be dependent on genetic susceptibility factors, history of prior psychological trauma, or an additional physical injury at the time of the traumatic event such as traumatic brain injury (TBI).

NEUROBIOLOGY OF PTSD

The neurobiology of PTSD is complex and involves neuroendocrine, neurochemical and neuroanatomical changes in neural networks.

Neuroendocrine Features:

The hypothalamic-pituitary-adrenal (HPA) axis is the central coordinator of how humans respond to stress. The stress response starts in the hypothalamus where paraventricular neurons (PVN) secrete corticotropin-releasing hormone (CRH).


This hormone stimulates the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary, which in turn stimulates the release of glucocorticoids (e.g. cortisol) from the adrenal cortex.

Cortisol exerts a negative feedback control of the HPA. Cortisol also reduces the noradrenergic stress response.

Sustained cortisol exposure has an adverse effect on the brain, particularly hippocampal neurons, resulting in impaired neurogenesis and neuroplasticity.

The hippocampus and pre-frontal cortex have an inhibitory effect on HPA while the amygdala and aminergic brain stem neurons stimulate the HPA.

Cortisol [1], [2]

In PTSD, there exists a dysregulation of glucocorticoid signalling underpinned by heightened negative feedback sensitivity of the HPA. This results in low cortisol levels and blunted ACTH responses to CRH due to elevated levels of CRH resulting in down-regulation of CRH receptors on the anterior pituitary.

Two genes that are thought to be involved are NR3C1 (encoding the glucocorticoid (GC) receptor) and FKBP5 (role in immunoregulation and regulating the amount of GC available to the GC receptor)

Evidence suggests that low cortisol at the time of exposure to trauma may predict the development of PTSD and that hypocortisolaemia may be a risk factor for the development of PTSD. This may explain why high dose hydrocortisone IV after trauma may prevent the development of PTSD. [3]


Neurochemical Features: [1], [2]

Serotonin

Decreased serotonin transmission in the dorsal and median raphe is related to hyper-vigilance, increased aggression, impulsivity as well as the enhanced formation and resilience of intrusive memories providing a role for SSRI’s in the treatment of PTSD.

3,4-Methylenedioxymethamphetamine (MDMA) is being studied in the treatment of PTSD as it increases serotonin levels. [4]

Noradrenaline

Noradrenaline (NA) mediates the stress response through central and peripheral mechanisms.

In PTSD there is increased noradrenaline transmission in networks that connect the locus coeruleus to the amygdala and hypothalamus (the noradrenergic feed-forward circuit).

The enhanced NA release is associated with increased fear conditioning and enhanced encoding of emotional memories with increased arousal and vigilance.

For example, yohimbine, a α2-adrenergic receptor antagonist, increases NA release inducing flashbacks and increased autonomic responses in patients with PTSD.

Along the same lines, propranolol administration (β2-adrenergic antagonist) after exposure to trauma can reduce PTSD symptom severity and reactivity to trauma cues.


Dopamine

Dopamine is implicated in the regulation of fear conditioning and anxiety. In individuals with PTSD, there is a genetic component associated with dopamine metabolism that governs whether an individual develops PTSD as well as what symptoms they may display.

Others

Glutamate (excitatory) release via the NMDA receptors involved in synaptic plasticity, learning and memory.

GABA (inhibitory) release mediating anti-anxiety effects. Proinflammatory cytokines involved in neuroinflammation (see:

Neuroinflammation Simplified – The Link Between the Immune System and the Brain)

Endocannabinoids (anandamide, 2-arachidonoylglycerol) mediate memory consolidation via CB1 receptors.

Neurosteroids (allopregnanolone) have an inhibitory effect on glucocorticoid and NA signalling.

Neuropeptides (neuropeptide Y, enkephalin endorphins, BDNF and DHEA)

Neuro-anatomic Features

Using structural brain imaging, circuits that are associated with adaptation to stress and fear conditioning have been shown to be structurally altered in patients with PTSD.

Hippocampus

Reduced hippocampal volume is a hallmark feature of PTSD. The hippocampus plays an important role in fear extinction and conditioning, stress responses and declarative memory.

Stress via enhanced cortisol secretion is known to impair hippocampal neurogenesis and damage hippocampal neurons which may explain the smaller hippocampal sizes found in patients with PTSD. [5]

A recent study, however, postulates that smaller hippocampal (left) volume is a risk factor in the persistence of PTSD as opposed to a result of PTSD. [6]

Amygdala

The amygdala plays a crucial role in emotional processing and the acquisition of fear responses.

The amygdala remembers a stressful response by increasing glutamate transmission which consolidates the traumatic memory via NMDA receptor


activity. Upon future exposure to a traumatic reminder, a fear response is activated.

Structural MRI analysis has revealed pathological damage to the amygdala, which was associated with a hyper-responsive reaction to subliminally threatening cues. [7]

Individuals with PTSD may show hypo- and hyper-activity within distinct regions of the amygdala sub-nuclei.

Downstream from the amygdala is the Periaqueductal gray (PAG) which is an important site mediating fear responses such as flight/ fight or freeze responses.

Medial prefrontal cortex (PFC)

The medial PFC (contains the anterior cingulate cortex (ACC)) is connected to the amygdala and has inhibitory control over its stress responses and emotional reactivity to different stimuli.

The medial prefrontal cortex mediates fear extinction through inhibition of acquired fear responses.

Decreased frontal cortex and ACC volumes are found in patients with PTSD. In PTSD, a decreased PFC volume correlates with symptom severity due to

decreased inhibitory control over the amygdalar stress response.


PTSD PHENOTYPES

The dynamic interaction between the medial prefrontal cortex and the amygdala creates two distinct phenotypes in PTSD patients. [1]

INTEGRATED MODEL OF PTSD

Three key brain networks have been identified as central to higher cognitive function:

Salience network (detection of salient internal and external stimuli) Default mode network (emotional regulation, social cognition, future thinking

and autobiographical memory) Central executive network (cognitive function)

The anterior insula acts as a switch between engaging the executive network and disengaging the default mode network allowing for better functioning of higher cognitive processes.

Abnormalities in these three areas are associated with specific clinical symptoms in PTSD as shown in the diagram below. [1]


TREATMENT

PTSD develops through a combination of psychological and biological mechanisms.

Treatment modalities aim to address the various psychological and biological components.

In some cases, a combination of medication and psychotherapy is required.


Two important concepts in PTSD treatment are:

1. Kindling – Process through which increasingly low severity stimuli can activate negative responses over time

2. Sensitisation – When people are repeatedly exposed to negative stimuli, progressively greater responses develop over time.

Treatment aims to achieve fear extinction, desensitisation and intervene in the kindling process.

Psychotherapy

Psychotherapy is considered a first-line therapy and can be divided into trauma-focused, and non-trauma focused psychotherapy.

Trauma-focused CBT has been most extensively studied and shown to be effective.

Prolonged exposure therapy and cognitive processing therapy are two types of trauma-focused CBT. They are based on the principles of extinction learning, habituation and desensitisation.

Trauma-focused therapy

Prolonged Exposure therapy: Progressive exposure to the trauma narrative and trigger settings.

Cognitive-processing therapy: Involves writing a trauma narrative and repeatedly reading it as a means to expose the trauma memory. It also addresses shame, guilt or feelings of mistrust. In this sense, culturally-adapted CBT has also been useful as this technique offers a more specific paradigm to treat PTSD.

Narrative exposure therapy: A short-term approach that involves the chronological cataloguing of their life and an in-depth detailing of all traumatic events. This therapy was developed for the survivors of the Pinochet regime in Chile and has proven to be very useful in overcoming trauma.

Eye Movement Desensitization and Reprocessing (EMDR)

EMDR is a “A therapy aiming to process distressing memories by having the patient recall distressing images while receiving one of several types of bilateral sensory input, including side-side eye movements” – Yehuda et al., 2015


Non-trauma-focused therapy

Supportive therapy Non-directive counselling Mindfulness and patient centred therapy Interpersonal therapy Yoga and mindfulness training

“Patients with a history of interpersonal violence, early life trauma or those with a complex presentation of PTSD that includes emotional detachment might be better treated with phase-oriented approaches.

Phase oriented approaches involve skills training, mood regulation and grounding, identifying attachment schemas an developing competence in social interactions.

Once these skills have been developed, the patient can then participate in modified exposure-based therapy focusing on emotional stability and negative personal schemas.” – Yehuda et al., 2015

This type of PTSD is often called complex trauma disorder or complex PTSD. Prof. Kulkarni talks about trauma and complex trauma disorder in women. A/Prof. Sathya Rao discusses the overlap of complex trauma disorder with Borderline Personality Disorder. (see: Inside the Mind of a Specialist in Borderline Personality Disorder)

Pharmacotherapy [1]

“Current evidence favours selective serotonin reuptake inhibitors as the class with the most evidence supporting their use as first-line psychopharmacological treatment options.” – Yehuda et al., 2015

A recent systematic review, commissioned by the WHO, showed that although some SSRIs are statistically superior to placebo, the effect size is small. [8]

When reviewing methodologically robust pharmacotherapy trials, Hoskins and colleagues found that only fluoxetine, paroxetine, and venlafaxine have statistically significant data on reducing PTSD symptoms compared to placebo.

Many other interventions are currently used off-label for the treatment of PTSD, and these drugs are based on the neurobiology of PTSD symptoms. These include:

Antidepressants – In addition to paroxetine and sertraline, phenelzine, imipramine, desipramine, amitriptyline, fluoxetine, brofaromine, bupropion and mirtazapine are the favoured first-line treatment option.


Antipsychotics – Dopaminergic blockade with risperidone, olanzapine, and quetiapine, however, cardiovascular and metabolic side-effects mean that extra caution is advised when prescribing these agents.

Anticonvulsants – Valproate, carbamazepine, phenytoin, phenobarbital, lamotrigine, topiramate, and tiagabine can be prescribed as monotherapy or as an adjunctive treatment for their GABA potentiating and anti-kindling effect.

Anti-adrenergic drugs (α1, α2 and β receptors) – Examples include prazosin, guanfacine, alfuzosin, doxazosin, propranolol and clonidine, which have been used as a treatment strategy for PTSD-related nightmares.

Other experimental treatment – D-cycloserine (glycine receptor agonist), endocannabinoids, neuropeptides (NPY antagonists, cholecystokinin antagonists, substance P antagonist, and nalmefene (endogenous opioid antagonist)), ketamine (see: Your Quick Guide to Ketamine in Depression and a Study That Questions It’s Known Mechanism of Action), mifepristone and hydrocortisone

Clinical Pearl:

PTSD is co-morbid unless proven otherwise. Diagnostic overshadowing, whereby symptoms are attributed only to trauma, may result in mis-diagnosis and inadequate treatment.

It is therefore crucial for clinicians to diagnose and treat any other co-morbid conditions.

CONCLUSION

Traumatic stress has a broad range of effects on the function and structure of discrete regions of the brain that have critical roles in emotion, memory, and reactivity.

PTSD is best understood as a heterogenous disorder with different phenotypes based on the brain circuits involved. Co-morbidity is high and clinicians should always be vigilant for the presence of other psychiatric disorders.

References

1. Yehuda R et al., Post-traumatic stress disorder. Nature Reviews. 2015

2. Sherin J and Nemeroff C. Post-traumatic stress disorder: the neurobiological impact of psychological trauma. Dialogues in Clinical Neuroscience. 2011

3. Zohar, J., Yahalom, H., Kozlovsky, N., Cwikel-Hamzany, S., Matar, M. A., Kaplan, Z., … & Cohen, H. (2011). High dose hydrocortisone immediately after trauma may alter the


trajectory of PTSD: interplay between clinical and animal studies. European Neuropsychopharmacology, 21(11), 796-809.

4. Sessa, B. (2017). MDMA and PTSD treatment:“PTSD: From novel pathophysiology to innovative therapeutics”. Neuroscience letters, 649, 176-180.

5. Bremner J et al., MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. American Journal of Psychiatry. 2011

6. Van Rooij, S. J. H., Kennis, M., Sjouwerman, R., Van Den Heuvel, M. P., Kahn, R. S., & Geuze, E. (2015). Smaller hippocampal volume as a vulnerability factor for the persistence of post-traumatic stress disorder. Psychological medicine, 45(13), 2737-2746.

7. Koenigs M and Grafman J. Post-traumatic stress disorder: The role of medial prefrontal cortex and amygdala. Neuroscientist. 2009

8. Hoskins M et al., Pharmacotherapy for post-traumatic stress disorder: systematic review and meta-analysis. British Journal of Psychiatry. 2015

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